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Paxlovid
Sponsor
ARTGs
Device/Product name
Paxlovid
Active Ingredient
Nirmatrelvir/ritonavir
Date of decision
Published
Submission type
New chemical entity
ATC codes
J05AE03 (ritonavir), Not yet assigned (nirmatrelvir)
Decision
Approved for provisional registration
What was the decision based on
The decision was based on quality (chemistry and manufacturing), nonclinical (pharmacology and toxicology), clinical (pharmacology, safety and efficacy) and risk management plan information submitted by the sponsor. The benefit-risk profile of Paxlovid was considered favourable for the therapeutic use approved.
What steps were involved in the decision process
Registration timeline
The following table summarises the key steps and dates for this application.
Data was provided as a rolling submission. Under normal circumstances, the TGA's assessment (for both provisional and general registration) begins once all information to support registration is available. As part of the Department of Health's response to the pandemic, the TGA has agreed to accept rolling data for COVID 19 vaccines and treatments, to enable early evaluation of data as it comes to hand.
| Description | Date |
|---|---|
| Determination (Provisional) | 1 October 2021 |
| Submission dossier accepted and first round evaluation commenced | 23 November 2021 |
| Evaluation completed | 6 January 2022 |
| Delegate's overall benefit-risk assessment and request for Advisory Committee advice | 7 January 2022 |
| Sponsor's pre-Advisory Committee response | 10 January 2022 |
| Advisory Committee meeting | 13 January 2022 |
| Registration decision (Outcome) | 18 January 2022 |
| Completion of administrative activities and registration on ARTG | 20 January 2022 |
| Number of working days from submission dossier acceptance to registration decision* | 35 |
*Statutory timeframe for standard applications is 255 working days
Date of entry onto ARTG
Original publication date
Black triangle scheme
Yes.As a provisionally registered product, this medicine will remain in the Black Triangle Scheme for the duration of its provisional registration.
Dose forms
Film-coated tablet
Strength
Each nirmatrelvir tablet contains 150 mg of nirmatrelvirEach ritonavir tablet contains 100 mg ritonavir
Other ingredients
Nirmatrelvir: microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, colloidal anhydrous silica, sodium stearylfumarate, Opadry complete film coating system 05B140011 pink.
Ritonavir: copovidone, calcium hydrogen phosphate, sorbitan monolaurate, colloidal anhydrous silica, sodium stearylfumarate, hypromellose, titanium dioxide, macrogol 400, hyprolose, purified talc, macrogol 3350, colloidal anhydrous silica, polysorbate 80.
Containers
Blister card
Pack sizes
A carton of 30 tablets in 5 blister cards, each blister card contains 4 nirmatrelvir and 2 ritonavir tablets
Routes of administration
Oral
Dosage
Nirmatrelvir must be taken together with ritonavir. Failure to correctly take nirmatrelvir with ritonavir will result in plasma levels of nirmatrelvir that will be insufficient to achieve the desired therapeutic effect.
The recommended dosage is 300 mg nirmatrelvir (two 150 mg tablets) with 100 mg ritonavir (one 100 mg tablet) taken together orally every 12 hours for 5 days.
Paxlovid should be taken as soon as possible after a diagnosis of COVID‑19 has been made and within 5 days of symptoms onset.
Paxlovid (both nirmatrelvir and ritonavir tablets) can be taken with or without food. The tablets should be swallowed whole and not chewed, broken, or crushed.
For further information refer to the Product Information.
Pregnancy category
B3Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed.Studies in animals have shown evidence of an increased occurrence of fetal damage, the significance of which is considered uncertain in humans.The use of any medicine during pregnancy requires careful consideration of both risks and benefits by the treating health professional. This must not be used as the sole basis of decision making in the use of medicines during pregnancy. The TGA does not provide advice on the use of medicines in pregnancy for specific cases. More information is available from obstetric drug information services in your State or Territory.
What was approved
Paxlovid (nirmatrelvir/ritonavir) was approved for the following therapeutic use:
Paxlovid has provisional approval for the treatment of coronavirus disease 2019 (COVID 19) in adults 18 years of age and older, who do not require initiation of supplemental oxygen due to COVID 19 and are at increased risk of progression to hospitalisation or death (see Section 5.1 Pharmacodynamic properties, clinical trials).
The decision has been made on the basis of short term efficacy and safety data. Continued approval of this indication depends on the efficacy and safety data from ongoing clinical trials and post-market assessment.
What is this medicine and how does it work
Nirmatrelvir is a peptidomimetic inhibitor of the Coronavirus disease (SARS-CoV-2) main protease (Mpro), also referred to as 3C-like protease (3CLpro) or nsp5 protease. Inhibition of SARS-CoV-2 Mpro renders the protein incapable of processing polyprotein precursors which leads to the prevention of viral replication. Nirmatrelvir was shown to be an inhibitor of SARS-CoV-2 Mpro (inhibitory constant (Ki)=3.1 nM, or total concentration of inhibitor needed to reach 50% inhibition (IC50)=19.2 nM) in a biochemical enzymatic assay. Nirmatrelvir was found to bind directly to the SARS-CoV-2 Mpro active site by X-radiation (X-ray) crystallography.Ritonavir inhibits the cytochrome P450, family 3, subfamily A (CYP3A)‑mediated metabolism of nirmatrelvir, thereby providing increased plasma concentrations of nirmatrelvir.
What post-market commitments will the sponsor undertake
Risk management plan (RMP)
Paxlovid (nirmatrelvir/ritonavir) is to be included in the Black Triangle Scheme. The Product Information (PI) and Consumer Medicine Information (CMI) for Paxlovid must include the black triangle symbol and mandatory accompanying text for the product’s entire period of provisional registration.
Any changes to which the sponsor has agreed should be included in a revised risk management plan (RMP) and Australian specific annex (ASA). However, irrespective of whether or not they are included in the currently available version of the RMP document, the agreed changes become part of the risk management system.
The Paxlovid European Union (EU)‑RMP (version 0.1, dated 30 November 2021; data lock point (DLP) 26 October 2021), with ASA (version 0.2, dated 23 December 2021), included with submission PM‑2021‑04880‑1‑2, and any subsequent revisions, as agreed with the TGA will be implemented in Australia.
An obligatory component of risk management plans is routine pharmacovigilance. Routine pharmacovigilance includes the submission of periodic safety update reports (PSURs).
Unless agreed separately between the supplier who is the recipient of the approval and the TGA, the first report must be submitted to TGA no later than 15 calendar months after the date of the approval letter. The subsequent reports must be submitted no less frequently than annually from the date of the first submitted report until the period covered by such reports is not less than three years from the date of this approval letter, or the entire period of provisional registration, whichever is longer.
The reports are to at least meet the requirements for PSURs as described in the European Medicines Agency's guideline on Good Pharmacovigilance Practices (GVP) module II PSUR (rev 1), part VII.B structures and processes. Note that submission of a PSUR does not constitute an application to vary the registration. Each report must have been prepared within ninety calendar days of the data lock point for that report.
Additional to the routine submission of the routine PSURs, expedited monthly, Paxlovid safety summary reports (including safety data for patients in Australia) are to be provided for the first 6 months post registration, and thereafter at intervals specified by the TGA.
Clinical
The following study reports/data will have to be submitted before a definitive authorisation can be considered:
- The sponsor must provide updates to the TGA regarding the clinical activity, efficacy, and effectiveness of Paxlovid against the current and future variants of concern and variants of interest identified by the World Health Organization (WHO).
- The sponsor must also provide updates to the TGA on timelines of the comparable overseas regulators for conditional and full marketing authorisation applications.
- When available, further data relating to efficacy in immunocompromised subjects, pregnant women, lactating mother, paediatric subjects, pharmacology, long term safety, drug-drug interaction, and the information relating to post market safety and effectiveness studies should be provided to the TGA to update the PI.
Confirmatory trial data (as identified in the sponsor's plan to submit comprehensive clinical data on the safety and efficacy of the medicine before the end of the 6 years that would start on the day that registration would commence) must be provided. Specifically, the sponsor must conduct studies as described in the clinical study plan in version 0.2 (dated 23 December 2021) of the ASA.
- Any further data/analysis from the pivotal study C4671005 should be submitted to TGA
Further guidance for sponsors is available on the TGA website.